4(3H)-pteridinone compounds

ABSTRACT

The present invention relates to 4(3H)-pteridinones represented by the formula: ##STR1## in which X is an oxygen atom or a sulphur atom, Y is a hydrogen atom, a lower alkyl radical, especially a methyl radical, at the 6-position or a hydroxyl group at the 7-position, R 1  is a hydrogen atom, a lower alkyl radical, a substituted or unsubstituted phenyl radical, a benzyl radical, a methoxymethyl group, an acetyl group, a 2-acetoxyethyl group or a 2,2,2-trifluoroethyl group and R 2  is a hydrogen atom or a lower alkyl radical, especially a methyl radical. 
     Application of these compounds as anti-allergic drugs.

This is a division of copending parent application Ser. No. 07/501,104filed Mar. 29, 1990 now U.S. Pat. No. 5,167,949.

The present invention relates to 4(3H)-pteridinones, to processes bymeans of which they may be prepared and to their application in thetherapeutic field.

The biological role of 4(3H)-pteridinones is illustrated by the2-alkyl-4(3H)-pteridinones described by V. Liede et al. in German Patent2,232,098 and claimed for their diuretic and saluretic activity.

The compounds which are the subject of the invention are represented bythe general formula I ##STR2## in which X is an oxygen atom or a sulphuratom, Y is a hydrogen atom, a lower alkyl radical, especially a methylradical, at the 6-position or a hydroxyl group at the 7-position, R₁ isa hydrogen atom, a lower alkyl radical, a substituted or unsubstitutedphenyl radical, a benzyl radical, a methoxymethyl group, an acetylgroup, a 2-acetoxyethyl group or a 2,2,2-trifluoroethyl group and R₂ isa hydrogen atom or a lower alkyl radical, especially a methyl radical.

The term lower applied to an alkyl radical means that the radical may belinear or branched and that it can comprise from 1 to 4 carbon atoms.

The term substituted applied to a phenyl radical means that the radicalmay be substituted with one to three groups selected from lower alkyl,lower alkoxy, halogen, hydroxyl and acetyl.

The possible tautomeric forms of the compounds of the invention form anintegral part of the invention. By way of example, but not exclusively,when Y is a hydroxyl group at the 7-position, the compounds of theinvention of the formula Ia may also be written according to thetautomeric form of the formula Ib. ##STR3##

The compounds in the formula of which X is an oxygen atom, Y is ahydrogen atom or a hydroxyl group at the 7-position and R₂ is a hydrogenatom constitute a class of particular interest.

Preferred radicals R₁ are lower alkyl radicals, the phenyl radical orthe benzyl radical.

The pharmaceutically acceptable salts also form an integral part of theinvention. These can be alkali metal salts. These salts are obtained bytreating the compounds of the invention with alkali metal hydroxides orcarbonates. Alkali metals is understood to mean metals such as sodium orpotassium.

The compounds of the invention may be prepared according to at least oneof the following methods:

a) A 3-amino-2-pyrazinecarboxamide of the formula II ##STR4## may becondensed with an ortho ester of the formula III

    R.sub.1 XCH.sub.2 C(OR.sub.3).sub.3                        III

In the formulae II and III, X, Y, R₁ and R₂ have the meanings givenabove. In the formula III, R₃ is a lower alkyl radical, preferably anethyl radical. The reaction is performed in acetic anhydride in thepresence of an excess of ortho ester of the formula III. The temperatureis the boiling point of the reaction mixture. The reaction time isgenerally between 1 and 3 hours.

b) When R₂ is a hydrogen atom, a 4-aminopteridine of the formula IV##STR5## may be hydrolyzed in dilute aqueous alkali. In the formula IV,X, Y and R₁ have the meanings given above. The reaction is performed inwater in the presence of a base such as sodium hydroxide or potassiumhydroxide. The temperature can vary between room temperature and theboiling point of the reaction mixture, and preferably between 75° C. andthe boiling point of the reaction mixture. The reaction time isgenerally between 10 minutes and 14 hours.

c) When Y and R₂ are hydrogen atoms, a 5,6-diamino-4(3H)-pyrimidinone offormula V ##STR6## is condensed with glyoxal. In the formula V, X and R₁have the meanings given above. The reaction is performed in water. Thetemperature can vary between room temperature and the boiling point ofthe reaction mixture. The reaction time is generally between 1 and 24hours.

d) In the special case where X is an oxygen atom, Y is a hydrogen atom,R₁ a 2-acetoxyethyl group and R₂ a hydrogen atom, the correspondingcompound of the invention I may be obtained by the hydrolysis followedby the acetylation of the compound IV for which X is an oxygen atom, Y ahydrogen atom and R₁ a 2-hydroxyethyl group.

e) In the special case where X is an oxygen atom and Y a hydroxyl groupat the 7-position and where R₁ and R₂ are hydrogen atoms, thecorresponding compound of the invention I may be obtained by hydrolysisof the compound of the same formula except for R₁, which represents anacetyl group.

The intermediate 3-amino-2-pyrazinecarboxamides of the formula II areknown compounds. The intermediate ortho esters of the formula III are,in most instances, known compounds. Those which are new were preparedaccording to the usual techniques described, in particular, by S. M.McElvain and J. W. Nelson, J. Am. Chem. Soc. 1942, 64, 1825.

The intermediate 4-aminopteridines of the formula IV are new compounds.They are prepared by condensation of a 3-amino-2-pyrazinecarbonitrile ofthe formula VI ##STR7## with an acetamidine of the formula VII ##STR8##In the formulae VI and VII, X, Y and R₁ have the meanings given above.

In the special case where X is an oxygen atom, Y a hydroxyl group at the7-position and R₁ a methoxymethyl group, the corresponding4-aminopteridine XI is obtained according to the reaction scheme below:##STR9## 3-Amino-5-chloro-2-pyrazinecarbonitrile VIII is condensed with2-(methoxymethoxy)acetamidine IX in the presence of methanol to give4-amino-7-methoxy-2-(methoxymethoxymethyl)pteridine of the formula X.The methoxy group at the 7-position of the compound X may be hydrolyzedselectively in an alkaline medium to yield4-amino-2-methoxymethoxymethyl-7-pteridinol of the formula XI.

The intermediate 3-amino-2-pyrazinecarbonitriles of the formula VI areknown compounds. The intermediate acetamidines of the formula VII are,in some instances, known compounds. Those which are new were preparedaccording to the usual techniques, by reaction of ammonia with the alkylacetimidates of the formula XII ##STR10## in an anhydrous low molecularweight alcohol such as methanol or ethanol In the formula XII, X and R₁have the meanings given above and R₄ is an alkyl radical, preferably amethyl radical or an ethyl radical.

The intermediate alkyl acetimidates of the formula XII are, in someinstances, known compounds. Those which are new were prepared accordingto the usual techniques described, in particular, by C. Djerassi and C.R. Scholz, J. Am. Chem. Soc. 1947, 69, 1688 and by F. C. Schaefer and G.A. Peters, J. Org. Chem,. 1961, 26, 412.

In the special case where X is an oxygen atom, R₁ a 2-hydroxyethyl groupand R₄ an ethyl radical, the corresponding alkyl acetimidate XII isobtained according to a variant of the method of F. C. Schaefer and G.A. Peters, starting with (2-acetoxyethoxy)acetonitrile.

In the special case where X is an oxygen atom and where R₁ and R₄ areethyl radicals, the corresponding alkyl acetimidate XII may be obtainedby reaction of chloroacetonitrile with sodium ethoxide and ethanol.

The 5,6-diamino-4(3H)-pyrimidinones of the formula V are new compounds.They are prepared according to the reaction scheme below: ##STR11## Anacetamidine of the formula VII is condensed with the imino ether ofethyl cyanoacetate XIII to give a 6-amino-4(3H)-pyrimidinone of theformula XIV. These compounds XIV are nitrosated to6-amino-5-nitroso-4(3H)-pyrimidinones of the formula XV Reduction of thecompounds of the formula XV with sodium dithionite or by catalytichydrogenation yields the 5,6-diamino-4(3H)-pyrimidinones V.

The compounds represented by the general formula I possess excellentanti-allergic properties, and are superior to known products, especiallyby virtue of being active when administered orally.

The anti-allergic activity was measured in rats by the passive cutaneousanaphylaxis or PCA test described by I. Mota, Life Sciences 1963, 7, 465and Z. Ovary et al., Proceedings of Society of Experimental Biology andMedicine 1952, 81, 584.

In this test, the skin of rats is sensitized by 4 intradermal injectionsof a homologous anti-ovalbumin serum diluted 15-fold. On the dayfollowing sensitization, the animals receive 1 ml/kg of a 2.5% salinesolution of Evans blue and 1 ml/kg of a 2.5% saline solution ofovalbumin simultaneously by intravenous injection. The test compoundsare administered before the antigen, the time interval being 5 min byintraperitoneal injection and 10 min by the oral route. Thirty minutesafter injection of the ovalbumin/dye mixture, the animals are sacrificedand the intensity of the allergic response is determined by measuringthe area of skin coloration. The protection provided by the products ofthe invention is expressed as an ED₅₀ (dose decreasing by 50% the skinarea occupied by the dye). Four rats are used for each dose of products.

The results obtained intraperitoneally for a few products of theinvention are recorded in Table I.

                  TABLE I                                                         ______________________________________                                                      PCA                                                             PRODUCT       ED.sub.50 (mg/kg/IP)                                            ______________________________________                                        Example 1      7                                                              Example 3     14                                                              Example 4      9                                                              Example 7     21                                                              Example 9     39                                                              Example 11    10                                                              Example 12    18                                                              Example 13    14                                                              ______________________________________                                    

The products showing the best results intraperitoneally were testedorally. These results are recorded in Table II.

                  TABLE II                                                        ______________________________________                                                      PCA                                                             PRODUCT       ED.sub.50 (mg/kg/PO)                                            ______________________________________                                        Example 1     24                                                              Example 3     33                                                              Example 4     25                                                              Example 11    48                                                              ______________________________________                                    

The compounds described are distinguished, in addition, from knownproducts by their long duration of action and by a capacity foranagonizing the effects of PAF-acether, especially itsbronchoconstrictor effects. By way of illustration, the ED₅₀ of thecompound described in Example 1 when administered intravenously is 0.068mg/kg on the bronchospasm induced in anaesthetized guinea pigs byinjection of 10 ng/kg/IV of PAF-acether.

The compounds of the invention exhibit low toxicity. By way ofillustration, for the compound described in Example 1, the median lethaldoses determined orally on rats and on mice are above 2,000 mg/kg, andthe median lethal doses determined intraperitoneally and intraveneouslyon mice are above 1,600 mg/kg.

The present application also has as its subject the application of thecompounds I by way of drugs, and in particular anti-allergic drugs.These drugs may be administered by inhalation in the form of aerosols,orally in the form of tablets, sugar-coated tablets or hard gelatincapsules, intravenously in the form of an injectable solution,cutaneously in the form of ointment, powder or solution or rectally inthe form of suppositories. The daily dosages can vary from 1 to 50 mg ofactive principle taken by inhalation, from 5 to 250 mg of activeprinciple taken orally, from 1 to 50 mg of active principle takenintravenously and from 20 to 400 mg of active principle taken rectally.

A few pharmaceutical formulations are given below by way ofnon-restrictive examples:

    ______________________________________                                        Composition of a capsule for inhalation:                                      active principle         5       mg                                           Composition of an aerosol:                                                    active principle         1       g                                            propellent gases         99      g                                            Composition of a tablet:                                                      active principle         50      mg                                           excipient: lactose, wheat starch,                                             polyvidone, talc, magnesium stearate                                          Composition of a hard gelatin capsule:                                        active principle         50      mg                                           excipient: lactose, wheat starch,                                             talc, magnesium stearate                                                      Composition of an ampoule of injectable                                       solution:                                                                     active principle         10      mg                                           excipient: sorbitol, water for                                                                         5       ml                                           injections qs                                                                 Composition of a suppository:                                                 active principle         50      mg                                           semi-synthetic glycerides qs                                                                           500     mg                                           Composition of an ointment:                                                   active principle         0.5%                                                 polyoxyethylene glycol glyceryl                                                                        15%                                                  stearate                                                                      polyoxyethylenated saturated glycerides                                                                2%                                                   liquid paraffin          6%                                                   water qs                 100%                                                 ______________________________________                                    

The examples which follow illustrate the invention without impliedlimitation. In the nuclear magnetic resonance (NMR) data, the followingabbreviations were used: s for singlet, d for doublet; t for triplet, qfor quartet and m for unresolved peaks; the chemical shifts δ areexpressed in ppm.

Example 1 2-Ethoxymethyl-4(3H)-pteridinone

A mixture of 8.3 g (0.060 mole) of 3-amino-2-pyrazinecarboxamide[prepared according to R. C. Ellingson et al., J. Am. Chem. Soc. 1945,67, 1711], 49.5 g (0.24 mole) of triethyl orthoethoxyacetate [preparedaccording to S. M. McElvain and P. M. Walters, J. Am. Chem. Soc. 1942,64, 1963] and 53 ml of acetic anhydride is refluxed under a nitrogenatmosphere for 3 hours. The temperature of this reflux falls with thepassage of time from 124° to 96° C. and then remains constant at thelatter temperature. After cooling, the precipitate formed is isolated byfiltration. It is washed with ether and recrystallized from ethanol.Yld: 5.5 g (44%), m.p. 168°-169° C.

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.10 N.sub.4 O.sub.2 (FW = 206.21)                     C %        H %    N %                                               ______________________________________                                        calculated  52.42        4.89   27.17                                         found       52.14        4.91   27.34                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (CDCl₃): δ=1.3 (3H, t); 3.7 (2H, q); 4.6 (2H, s); 8.8 (1H, d); 8.9(1H, d); 10.3 (1H, peak exchangeable with CF₃ COOD).

EXAMPLE 2 2-Ethoxymethyl-4(3H)-pteridinone a) Methyl 2-ethoxyacetimidate

66.7 g (0.78 mole) of ethoxyacetonitrile [prepared according to L.Ramachandra Row and T. R. Thiruvengadam, Current Sci. 1947 (India), 16,379] are added to a solution of sodium methoxide in methanol, obtainedby reaction of 1.8 g (0.078 gram-atom) of sodium in 400 ml of methanol.The reaction mixture is stirred for 3 hours at room temperature. Thesodium methoxide is then neutralized with a stream of carbon dioxide andthe reaction mixture is thereafter concentrated under reduced pressure.The residue obtained is taken up with ether. The inorganic products areremoved by filtration; the ethereal filtrate is concentrated and theresidue is distilled under reduced pressure. Yld: 53.5 g (59%), b.p.₁₅38°-40° C.

NMR (CDCl₃): δ=1.2 (3H, t); 3.5 (2H, q); 3.7 (3H, s); 3.8 (2H, s); 7.6(1H, peak exchangeable with D₂ O).

b) 2-Ethoxyacetamidine

53.5 g (0.457 mole) of methyl 2-ethoxyacetimidate are added to asolution, maintained at 10° C., of 39 g (2.29 moles) of ammonia in 1225ml of absolute ethanol. The solution obtained is left for 6 days at roomtemperature and is then concentrated under reduced pressure. It is usedin the next step without further purification. Yld: 46.7 g(quantitative).

c) 4-Amino-2-(ethoxymethyl)pteridine

A mixture of 36.0 g (0.30 mole) of 3-amino-2-pyrazinecarbonitrile[prepared according to A. Albert and K. Ohta, J. Chem. Soc. C, 1970,1540] and 46.7 g of 2-ethoxyacetamidine in 700 ml of absolute ethanol isrefluxed for 2 hours 30 minutes under a nitrogen atmosphere. Aftercooling, the precipitate obtained is isolated by filtration. It ispurified by recrystallization from ethanol. Yld: 52.0 g (84%), m.p.152°-154° C.

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.11 N.sub.5 O (FW = 205.22)                           C %        H %    N %                                               ______________________________________                                        calculated  52.67        5.40   34.13                                         found       52.56        5.37   34.04                                         ______________________________________                                    

NMR (DMSO-d₆): δ=1.1 (3H, t); 3.5 (2H, q); 4.4 (2H, s); 8.2 (2H, peakexchangeable with CF₃ COOD); 8.7 (1H, d); 9.0 (1H, d).

d) 2-Ethoxymethyl-4(3H)-pteridinone

A solution of 30.0 g (0.146 mole) of 4-amino-2-(ethoxymethyl)pteridinein 800 ml of 5% aqueous sodium hydroxide is brought slowly to 75° C. andmaintained at this temperature for 2 hours. After cooling, the solutionobtained is acidified with acetic acid to pH 6 and is then extractedwith chloroform. The organic extracts are dried over sodium sulphate andconcentrated to dryness under reduced pressure. The solid residue isrecrystallized from ethanol in the presence of Norit. Yld: 19.5 g (65%),m.p.=168°-169° C. The product is identical to that obtained in Example1.

Example 3 2-Methoxymethyl-4(3H)-pteridinone

Obtained using the procedure described in Example 1, starting with 11.7g (0.085 mole) of 3-amino-2-pyrazinecarboxamide, 73.0 g (0.38 mole) oftriethyl orthomethoxyacetate [prepared according to E. T. Stiller, U.S.Pat. No. 2,422,598; C.A. 1947, 41, 5904a] and 75 ml of acetic anhydride.Yld: 12.3 g (75%), m.p. 187°-189° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.8 H.sub.8 N.sub.4 O.sub.2 (FW = 192.18)                      C %        H %    N %                                               ______________________________________                                        calculated  50.00        4.20   29.15                                         found       49.92        4.10   29.12                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=3.4 (3H, s); 4.4 (2H, s); 8.8 (1H, d); 9.0 (1H, d);12.7 (1H, peak exchangeable with CF₃ COOD).

Example 4 2-Propoxymethyl-4(3H)-pteridinone a) Ethyl2-propoxyacetimidate hydrochloride

Hydrogen chloride gas is bubbled for one hour into a solution, cooled to0° C., of 29.7 g (0.30 mole) of propoxyacetonitrile [prepared accordingto D. Gauthier, Compt. Rend. Acad. Sci. 1906, 143, 831] and 13.8 g (0.30mole) of absolute ethanol in 500 ml of ether. The reaction mixture isthen left for 2 days at 0° C. and is thereafter taken up with 300 ml ofether. The precipitate formed is isolated by filtration. It is washedwith ether and dried under reduced pressure; it is used in the next stepwithout further purification. Yld: 30.2 g (55%).

b) Triethyl orthopropoxyacetate

30.2 g (0.17 mole) of ethyl 2-propoxyacetimidate hydrochloride aredissolved in 160 ml of absolute ethanol. The solution is left for 2 daysat room temperature; it is then concentrated under reduced pressure. Theresidue obtained is taken up with ether and filtered. The etherealsolution is dried over potassium carbonate, filtered and concentratedunder reduced pressure. The liquid obtained is used in the next stepwithout further purification. Yld: 29.3 g (80%).

NMR (CDCl₃): δ=0.9 (3H, t); 1.3 (9H, t); 1.3-2.0 (2H, m); 3.4 (2H, t);3.5 (2H, s); 3.6 (6H, q).

c) 2-Propoxymethyl-4(3H)-pteridinone

Obtained using the procedure described in Example 1, starting with 4.6 g(0.033 mole) of 3-amino-2-pyrazinecarboxamide, 29.3 g (0.133 mole) oftriethyl orthopropoxyacetate and 30 ml of acetic anhydride. Yld: 2.6 g(36%), m.p. 158°-160° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.10 H.sub.12 N.sub.4 O.sub.2 (FW = 220.23)                    C %        H %    N %                                               ______________________________________                                        calculated  54.54        5.49   25.44                                         found       54.55        5.45   25.68                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=0.9 (3H, t); 1.3-2.0 (2H, m); 3.5 (2H, t); 4.4 (2H, s);8.8 (1H, d); 9.0 (1H, d); 12.7 (1H, peak exchangeable with CF₃ COOD).

Example 5 2-Methoxymethyl-3-methyl-4(3H)-pteridinone

A mixture of 7.8 g (0.0513 mole) of3-amino-N-methyl-2-pyrazinecarboxamide [prepared according to W. F. Keiret al., J. Chem. Soc., Perkin Trans 1, 1978, 1002], 39.4 g (0.205 mole)of triethyl orthomethoxyacetate and 45.3 ml of acetic anhydride isrefluxed under a nitrogen atmosphere for 3 hours. The temperature ofthis reflux falls with the passage of time from 114° to 90° C. and thenremains constant at the latter temperature. After cooling, the reactionmixture is concentrated to dryness under reduced pressure. The residueobtained is purified by chromatography on a silica column (eluent:chloroform/methanol, 95:5 and then 90:10), and is then recrystallizedfrom ethyl acetate. Yld: 5.0 g (47%), m.p. 130.5°-132.5° C.

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.10 N.sub.4 O.sub.2 (FW = 206.21)                     C %        H %    N %                                               ______________________________________                                        calculated  52.42        4.89   27.17                                         found       52.51        4.94   27.17                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=3.4 (3H, s); 3.6 (3H, s); 4.7 (2H, s); 8.9 (1H, d); 9.0(1H, d).

Example 6 2-Acetoxymethyl-4(3H)-pteridinone a) Ethyl2-acetoxyacetimidate hydrochloride

Hydrogen chloride gas is bubbled to saturation into a solution, cooledto 0° C., of 30.0 g (0.303 mole) of acetoxyacetonitrile [preparedaccording to L. Henry, Rec. Trav. Chim. Pays Bas 1905, 24, 169] and 15.4g (0.334 mole) of absolute ethanol in 300 ml of ether. The reactionmixture is then left for 5 hours at 0° C. The precipitate formed isisolated by filtration. It is washed with ether and dried under reducedpressure; it is used in the next step without further purification. Yld:52.2 g (95%), m.p. 100°-101° C.

NMR (DMSO-d₆ +CF₃ COOD): δ=1.1 (3H, t); 1.7 (3H, s); 3.4 (2H, q); 3.8(2H, s).

b) Triethyl orthoacetoxyacetate

A mixture of 34.0 g (0.187 mole) of ethyl 2-acetoxyacetimidatehydrochloride and 340 ml of absolute ethanol is left for 3 days at roomtemperature. The precipitate formed is removed by filtration; thefiltrate is concentrated under reduced pressure. The residue obtained istaken up with 800 ml of ether and cooled to about -10° C. A newprecipitate is formed, and is removed by filtration. The filtrate isconcentrated under reduced pressure. The liquid obtained is used in thenext step without further purification. Yld: 34.5 g 84%).

NMR (CDCl₃): δ=1.0 (9H, t); 1.9 (3H, s); 3.4 (6H, q); 4.1 (2H, s).

c) 2-Acetoxymethyl-4(3H)-pteridinone

Obtained using the procedure described in Example 1, starting with 5.3 g(0.038 mole) of 3-amino-2-pyrazinecarboxamide, 34.5 g (0.157 mole) oftriethyl orthoacetoxyacetate and 34.5 ml of acetic anhydride. Refluxingtime: 1 hour 45 minutes. Yld: 5.4 g (65%), m.p. 210°-212° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.8 N.sub.4 O.sub.3 (FW = 220.19)                      C %        H %    N %                                               ______________________________________                                        calculated  49.09        3.66   25.45                                         found       49.02        3.73   25.56                                         ______________________________________                                    

IR: ν(C=O)=1670 and 1720 cm⁻¹

NMR (DMSO-d₆): δ=2.2 (3H, s); 5.0 (2H, s); 8.8 (1H, d); 9.0 (1H, d);13.8 (peak exchangeable with CF₃ COOD).

Example 7 2-Ethoxymethyl-7-hydroxy-4(3H)-pteridinone

Obtained using the procedure described in Example 1, starting with 2.1 g(0.0136 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide [preparedaccording to E. C. Taylor et al., J. Org. Chem. 1975, 40, 2341], 14.0 g(0.068 mole) of triethyl orthoethoxyacetate and 14.0 ml of aceticanhydride. Yld: 1.2 g (40%), m.p. 255°-256° C.(methanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.10 N.sub.4 O.sub.3 (FW = 222.20)                     C %        H %    N %                                               ______________________________________                                        calculated  48.65        4.54   25.21                                         found       48.88        4.56   25.14                                         ______________________________________                                    

IR: ν(C=O)=1640 and 1690 cm⁻¹

NMR (DMSO-d₆): δ=1.1 (3H, t); 3.5 (2H, q); 4.3 (2H, s); 7.9 (1H, s);12.7 (2H, broad peak).

Example 8 2-Acetoxymethyl-7-hydroxy-4(3H)-pteridinone

Obtained using the procedure described in Example 1, starting with 5.0 g(0.0324 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide, 29.5 g (0.134mole) of triethyl orthoacetoxyacetate and 9.5 ml of acetic anhydride.Refluxing time: 1 hour 45 minutes. Yld: 3.8 g (50%), m.p.>300° C.(ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.8 N.sub.4 O.sub.4 (FW = 236.19)                      C %        H %    N %                                               ______________________________________                                        calculated  45.77        3.41   23.72                                         found       45.79        3.65   23.84                                         ______________________________________                                    

IR: ν(C=O)=1625, 1690 and 1735 cm⁻¹

NMR (DMSO-d₆): δ=2.2 (3H, s); 5.0 (2H, s); 7.9 (1H, s); 12.9 (2H, peakexchangeable with CF₃ COOD).

Example 9 2-Phenoxymethyl-4(3H)-pteridinone a)4-Amino-2-(phenoxymethyl)pteridine

Obtained using the procedure described in section c of Example 2,starting with 3.0 g (0.025 mole) of 3-amino-2-pyrazinecarbonitrile and3.8 g (0.025 mole) of 2-phenoxyacetamidine [prepared according to C.Djerassi and C. R. Scholz, J. Am. Chem. Soc., 1947, 69, 1688] in 100 mlif absolute ethanol. Refluxing time: 4 hours. Yld: 5.4 g (85%), m.p.202°-204° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.11 N.sub.5 O (FW = 253.26)                          C %        H %    N %                                               ______________________________________                                        calculated  61.65        4.38   27.65                                         found       61.28        4.22   27.37                                         ______________________________________                                    

NMR (DMSO-d₆): δ=5.1 (2H, s); 6.6-7.6 (5H, m); 8.4 (2H, peakexchangeable with CF₃ COOD); 8.8 (1H, d); 9.0 (1H, d).

b) 2-Phenoxymethyl-4(3H)-pteridinone

A mixture of 4.0 g (0.016 mole) of 4-amino-2-(phenoxymethyl)pteridineand 400 ml of 5% aqueous sodium hydroxide is brought slowly to 95° C.and maintained at this temperature for 2 hours. After cooling, thesolution obtained is acidified with acetic acid to pH 5.5. Theprecipitate formed is isolated by filtration. It is purified byrecrystallization from ethanol. Yld: 2.8 g (70%), m.p. 220°-221° C.

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.10 N.sub.4 O.sub.2 (FW = 254.25)                    C %        H %    N %                                               ______________________________________                                        calculated  61.41        3.96   22.04                                         found       61.44        3.97   22.08                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=5.0 (2H, s); 6.7-7.4 (5H, m); 8.7 (1H, d); 8.9 (1H, d);12.8 (1H, peak exchangeable with CF₃ COOD).

Example 10 2-[(2,3-Dichlorophenoxy)methyl]-4(3H)-pteridinone a) Ethyl2-(2,3-dichlorophenoxy)acetimidate hydrochloride

Obtained using the procedure described in section a of Example 6,starting with 219.8 g (1.086 moles) of (2,3-dichlorophenoxy)acetonitrile[prepared according to R. W. Fuller et al., J. Med. Chem. 1973, 16, 101]and 50.0 g (1.086 moles) of absolute ethanol in 1750 ml of ether.Reaction time: 16 hours at 0° C. Yld: 293.5 g (95%), m.p. 167°-169° C.

NMR (DMSO-d₆): δ=1.3 (3H, t); 4.3 (2H, q); 5.1 (2H, s); 6.6 (1H, sexchangeable with CF₃ COOD); 7.0-7.6 (3H, m); 8.3 (1H,s exchangeablewith CF₃ COOD).

b) 2-(2,3-Dichlorophenoxy)acetamidine hydrochloride

11.8 g (0.041 mole) of ethyl 2-(2,3-dichlorophenoxy)acetimidatehydrochloride are added rapidly to a solution, cooled to 10° C., of 3.5g (0.21 mole) of ammonia in 100 ml of absolute ethanol. The reactionmixture is left for 3 days at room temperature. After removal of a fewsuspended particles by filtration, the reaction mixture is concentratedto dryness under reduced pressure. The solid residue obtained ispurified by washing with ether and recrystallization from isopropanol.Yld: 8.0 g (75%), m.p. 204.5°-206.5° C.

    ______________________________________                                        Percentage analysis: C.sub.8 H.sub.9 Cl.sub.3 N.sub.2 O (FW = 255.53)                   C %  H %        Cl %    N %                                         ______________________________________                                        calculated  37.60  3.55       41.62 10.96                                     found       37.61  3.60       41.36 10.85                                     ______________________________________                                    

NMR (DMSO-d₆ +D₂ O): δ=5.1 (2H, s); 7.1-7.7 (3H, m)

c) 2-(2,3-Dichlorophenoxy)acetamidine

8.0 g (0.031 mole) of 2-(2,3-dichlorophenoxy)-acetamidine hydrochlorideare suspended in sodium hydroxide solution and extracted withchloroform. The organic extract is concentrated to dryness under reducedpressure. The solid residue is washed with hexane and dried; it is usedin the next step without further purification. Yld: 6.7 g (98%), m.p.104°-108° C.

d) 4-Amino-2-[(2,3-dichlorophenoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 3.6 g (0.030 mole) of 3-amino-2-pyrazinecarbonitrile and6.6 g (0.030 mole) of 2-(2,3-dichlorophenoxy)acetamidine in 100 ml ofabsolute ethanol. Refluxing time: 14 hours. Yld: 8.1 g (84%), m.p.216°-218° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.9 Cl.sub.2 N.sub.5 O (FW = 322.15)                  C %  H %        Cl %    N %                                         ______________________________________                                        calculated  48.47  2.82       22.01 21.74                                     found       48.38  2.86       22.10 21.81                                     ______________________________________                                    

NMR (DMSO-d₆): δ=5.2 (2H, s); 7.1 (3H, s); 8.3 (2H, peak exchangeablewith CF₃ COOD); 8.7 (1H, d); 9.0 (1H, d).

e) 2-[(2,3-Dichlorophenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 1.0 g (0.0031 mole) of4-amino-2-[(2,3-dichlorophenoxy)methyl]pteridine in 35 ml of 5% aqueoussodium hydroxide. Heating time: 10 minutes under reflux. Yld: 0.5 g(50%), m.p. 219°-220.5° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.8 Cl.sub.2 N.sub.4 O.sub.2 (FW =          323.14)                                                                                 C %  H %        Cl %    N %                                         ______________________________________                                        calculated  48.32  2.50       21.94 17.34                                     found       48.53  2.53       21.99 17.49                                     ______________________________________                                    

IR: ν(C=O)=1680 cm⁻¹

NMR (DMSO-d₆ +CF₃ COOD): δ=5.1 (2H, s); 7.1 (3H, s); 8.7 (1H, d); 8.9(1H, d).

Example 11 2-Benzyloxymethyl-4(3H)-pteridinone a)4-Amino-2-(benzyloxymethyl)pteridine

Obtained using the procedure described in section c of Example 2,starting with 12.0 g )0.10 mole) of 3-amino-2-pyrazinecarbonitrile and25.0 g (0.15 mole) of 2-(benzyloxy)acetamidine [prepared according to W.J. Haggerty Jr. and W. J. Rost, J. Pharm. Sci. 1969, 58, 50] in 400 mlof absolute ethanol. Refluxing time: 4 hours. Yld: 15.4 g (58%), m.p.112°-114° C. An analytical sample was obtained by recrystallization fromethanol, followed by washing with dilute hydrochloric acid and finallyrecrystallization from ethyl acetate. M.p. 131°-133° C.

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.13 N.sub.5 O (FW = 267.29)                          C %        H %    N %                                               ______________________________________                                        calculated  62.91        4.90   26.20                                         found       62.74        4.79   26.22                                         ______________________________________                                    

NMR (DMSO-d₆): δ=4.6 (2H, s); 4.7 (2H, s); 7.1-7.6 (5H, m); 8.3 (2H,peak exchangeable with CF₃ COOD); 8.8 (1H, d); 9.0 (1H, d).

b) 2-Benzyloxymethyl-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 10.0 g (0.037 mole) of crude4-amino-2-(benzyloxymethyl)pteridine in 300 ml of 5% aqueous sodiumhydroxide. Heating time: 2 hours at 80° C. Yld: 8.2 g (83%), m.p.157°-159° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.12 N.sub.4 O.sub.2 (FW = 268.28)                    C %        H %    N %                                               ______________________________________                                        calculated  62.68        4.51   20.88                                         found       62.85        4.39   21.15                                         ______________________________________                                    

IR: ν(C=O)=1680 cm⁻¹

NMR (DMSO-d₆): δ=4.5 (2H, s); 4.6 (2H, s); 7.1-7.6 (5H, m); 8.8 (1H, d);8.9 (1H, d); 12.7 (1H, peak exchangeable with CF₃ COOD).

Example 12 2-Methoxymethoxymethyl-4(3H)-pteridinone a) Methyl2-(methoxymethoxy)acetimidate

Obtained using the procedure described in section a of Example 2,starting with 286.8 g (2.84 moles) of methoxymethoxyacetonitrile[prepared according to D. J. Loder and W. M. Bruner, U.S. Pat. No.2,398,757; C.A. 1946, 40, 3774] and 6.5 g (0.284 gram-atom) of sodium in1430 ml of methanol. Reaction time: 2 days. Yld: 302.6 g (80%), b.p.₁₅62°-65° C.

NMR (CDCl₃): δ=3.3 (3H, s); 3.7 (3H, s); 3.9 (2H, s); 4.6 (2H, s); 7.7(1H, peak exchangeable with D₂ O).

b) 2-(Methoxymethoxy)acetamidine

Obtained using the procedure described in section b of Example 2,starting with 20.0 g (0.15 mole) of methyl 2-(methoxymethoxy)acetimidateand 13.0 g (0.75 mole) of ammonia in 400 ml of absolute ethanol.Reaction time: 2 days. Yld: 18.0 g (quantitative).

NMR (CDCl₃ +D₂ O): δ=3.4 (3H, s); 4.0 (2H, s); 4.6 (2H, s).

c) 4-Amino-2-(methoxymethoxymethyl)pteridine

Obtained using the procedure described in section c of Example 2,starting with 12.0 g (0.10 mole) of 3-amino-2-pyrazinecarbonitrile and18.0 g (0.15 mole) of 2-(methoxymethoxy)acetamidine in 400 ml ofabsolute ethanol. Refluxing time: 4 hours. Yld: 15.8 g (71%), m.p.129°-131° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.11 N.sub.5 O.sub.2 (FW = 221.22)                     C %        H %    N %                                               ______________________________________                                        calculated  48.86        5.01   31.66                                         found       49.02        5.20   31.61                                         ______________________________________                                    

NMR (DMSO-d₆): δ=3.3 (3H, s); 4.5 (2H, s); 4.7 (2H, s); 8.2 (2H, peakexchangeable with CF₃ COOD); 8.7 (1H, d); 8.9 (1H, d).

d) 2-Methoxymethoxymethyl-4(3H)-pteridinone

Obtained using the procedure described in section d of Example 2,starting with 5.3 g (0.024 mole) of4-amino-2-(methoxymethoxymethyl)pteridine in 250 ml of 5% aqueous sodiumhydroxide. Heating time: 2 hours at 80° C. Yld: 2.2 g (41%), m.p.161°-163° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.10 N.sub.4 O.sub.3 (FW = 222.20)                     C %        H %    N %                                               ______________________________________                                        calculated  48.65        4.54   25.21                                         found       48.38        4.52   24.92                                         ______________________________________                                    

IR: ν(C=O)=1680 cm⁻¹

NMR (DMSO-d₆): δ=3.2 (3H, s); 4.4 (2H, s); 4.7 (2H, s); 8.7 (1H, d); 8.9(1H, d); 12.6 (1H, peak exchangeable with CF₃ COOD).

Example 13 2-Isopropoxymethyl-4(3H)-pteridinone a)2-Isopropoxyacetamidine

Obtained using the procedure described in section b of Example 2starting with 14.7 g (0.112 mole) of methyl 2-isopropoxyacetimidate[prepared according to F. C. Schaefer and G. A Peters, J. Org. Chem.1961, 26, 412] and 9.50 g (0.56 mole) of ammonia in 300 ml of absoluteethanol. Reaction time: 2 days. Yld: 13.0 g (quantitative).

b) 4-Amino-2-(isopropoxymethyl)pteridine

Obtained using the procedure described in section c of Example 2,starting with 8.8 g (0.073 mole) of 3-amino-2-pyrazinecarbonitrile and13.0 g (0.11 mole) of 2-isopropoxyacetamidine in 295 ml of absoluteethanol. Refluxing time: 4 hours. Yld: 4.5 g (28%), m.p. 139°-141° C.(ethyl acetate).

    ______________________________________                                        Percentage analysis: C.sub.10 H.sub.13 N.sub.5 O (FW = 219.25)                          C %        H %    N %                                               ______________________________________                                        calculated  54.78        5.98   31.94                                         found       54.88        6.17   31.83                                         ______________________________________                                    

NMR (CDCl₃): 1.3 (6H, d); 3.8 (1H, septet); 4.7 (2H, s); 8.2 (2H, peakexchangeable with CF₃ COOD); 8.6 (1H, d); 9.0 (1H, d).

c) 2-Isopropoxymethyl-4(3H)-pteridinone

Obtained using the procedure described in section d of Example 2,starting with 4.5 g (0.0205 mole) of4-amino-2-(isopropoxymethyl)pteridine in 150 ml of 5% aqueous sodiumhydroxide. Heating time: 2 hours at 80° C. Yld: 3.0 g (66%), m.p.198°-199° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.10 H.sub.12 N.sub.4 O.sub.2 (FW = 220.23)                    C %        H %    N %                                               ______________________________________                                        calculated  54.54        5.49   25.44                                         found       54.24        5.20   25.29                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (CDCl₃): δ=1.3 (6H, d); 3.8 (1H, septet); 4.6 (2H, s); 8.7 (1H, d);8.9 (1H, d); 10.0 (1H, peak exchangeable with CF₃ COOD).

Example 14 2-[(2,2,2-Trifluoroethoxy)methyl]-4(3H)-pteridinone a)(2,2,2-Trifluoroethoxy)acetonitrile

At about 50° C., 26.4 g (0.40 mole) of 85% potassium hydroxide aresolubilized in 100 g (1.0 mole) of 2,2,2-trifluoroethanol. After coolingat 25° C., 37.8 g (0.50 mole) of chloroacetonitrile are added dropwiseto this solution. The temperature rises slowly to 40° C. and aprecipitate appears. The reaction mixture is then brought gradually to60° C.; after the addition of 300 ml of heptane, it is then brought toreflux. The whole of the vapour is condensed by means of a Dean andStark apparatus. The lower phase of the condensate is separated aftersettling has taken place and distilled at atmospheric pressure. Yld:19.6 g (28%), b.p. 125°-140° C.

NMR (CDCl₃): δ=3.9 (2H, q); 4.4 (2H, s).

b) Methyl 2-(2,2,2-trifluoroethoxy)acetimidate

Obtained using the procedure described in section a of Example 2,starting with 19.6 g (0.141 mole) of (2,2,2-trifluoroethoxy)acetonitrileand 0.3 g (0.013 gram-atom) of sodium in 95 ml of methanol. Reactiontime: 24 hours. Yld: 15.6 g (65%), b.p.₁₅ 44°-47° C.

NMR (CDCl₃): δ=3.8 (3H, s); 3.9 (2H, q); 4.0 (2H, s); 7.7 (1H, peakexchangeable with D₂ O)

c) 2-(2,2,2-Trifluoroethoxy)acetamidine

Obtained using the procedure described in section b of Example 2,starting with 15.6 g (0.091 mole) of methyl2-(2,2,2-trifluoroethoxy)acetimidate and 7.7 g (0.455 mole) of ammoniain 225 ml of absolute ethanol. Reaction time: 24 hours. Yld: 14.2 g(quantitative).

d) 4-Amino-2-[(2,2,2-trifluoroethoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 7.2 g (0.060 mole) of 3-amino-2-pyrazinecarbonitrile and14.2 g (0.091 mole) of 2-(2,2,2-trifluoroethoxy)acetamidine in 230 ml ofabsolute ethanol. Refluxing time: 7 hours. Yld: 6.5 g (42%), m p.145°-147° C. (ethyl acetate).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.8 F.sub.3 N.sub.5 O (FW = 259.19)                     C %  H %        F %    N %                                         ______________________________________                                        calculated   41.71  3.11       21.99                                                                              27.02                                     found        41.92  2.96       21.78                                                                              26.93                                     ______________________________________                                    

NMR (DMSO-d₆): δ=4.2 (2H, q); 4.6 (2H, s); 8.3 (2H, peak exchangeablewith CF₃ COOD); 8.7 (1H, m); 9.0 (1H, m).

e) 2-[(2,2,2-Trifluoroethoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section d of Example 2,starting with 5.0 g (0.0193 mole) of4-amino-2-[(2,2,2-trifluoroethoxy)methyl]pteridine in 105 ml of 5%aqueous sodium hydroxide. Heating time: 1 hour 30 minutes at 80° C. Yld:2.5 g (50%), m.p. 165°-167° C. (ethyl acetate).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.7 F.sub.3 N.sub.4 O.sub.2 (FW =            260.18)                                                                                  C %  H %        F %    N %                                         ______________________________________                                        calculated   41.55  2.71       21.91                                                                              21.53                                     found        41.53  2.68       21.78                                                                              21.32                                     ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆ +CF₃ COOD); δ=4.2 (2H, q); 4.6 (2H, s); 8.7 (1H, d); 8.9(1H, d).

Example 15 2-[(4-Chlorophenoxy)methyl]-4(3H)-pteridinone a)4-Amino-2-[(4-chlorophenoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 10.7 g (0.089 mole) of 3-amino-2-pyrazinecarbonitrile and24.5 g (0.133 mole) of 2-(4-chlorophenoxy)acetamidine [preparedaccording to C. Djerassi and C. R. Scholz, U.S. Pat. No. 2,517,468; C.A.1951, 45, 661f] in 320 ml of absolute ethanol. Refluxing time: 7 hours.Yld: 21.5 g (84%), m.p. 246°-248° C. (N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.10 ClN.sub.5 O (FW = 287.71)                        C %  H %        Cl %    N %                                         ______________________________________                                        calculated  54.27  3.50       12.32 24.34                                     found       54.25  3.50       12.37 24.33                                     ______________________________________                                    

NMR (DMSO-d₆): δ=5.1 (2H, s); 6.9 (2H, d); 7.3 (2H, d); 8.3 (2H, peakexchangeable with CF₃ COOD); 8.7 (1H, d); 9.0 (1H, d).

b) 2-[(4-chlorophenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 17.5 g (0.0608 mole) of crude4-amino-2-[(4-chlorophenoxy)methyl]pteridine in 1750 ml of 5% aqueoussodium hydroxide. Heating time: 1 hours 30 minutes under reflux. Yld:8.7 g (50%), m.p. 267°-269° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.9 ClN.sub.4 O.sub.2 (FW = 288.69)                   C %  H %        Cl %    N %                                         ______________________________________                                        calculated  54.09  3.14       12.28 19.41                                     found       54.04  2.94       12.42 19.20                                     ______________________________________                                    

IR: ν(C=O)=1675 cm⁻¹

NMR (CF₃ COOD): δ=5.5 (2H, s); 7.1 (2H, d); 7.4 (2H, d); 9.2 (1H, d);9.3 (1H, d).

Example 16 2-[(3,4-Dichlorophenoxy)methyl]-4(3H)-pteridinone a) Methyl2-(3,4-dichlorophenoxy)acetimidate

30.3 g (0.150 mole) of (3,4-dichlorophenoxy)-acetonitrile [preparedaccording to R. W. Fuller et al., J. Med. Chem. 1973, 16, 101] are addedto a solution of sodium methoxide in methanol, obtained by reaction of0.34 g (0.015 gram-atom) of sodium in 300 ml of methanol. The reactionmixture is stirred for 36 hours at room temperature. The sodiummethoxide is then neutralized with a stream of carbon dioxide, and thereaction mixture is thereafter concentrated to dryness under reducedpressure. The residue obtained is taken up with methylene chloride. Theinorganic products are removed by filtration; the organic filtrate isconcentrated to dryness under reduced pressure and the residue isrecrystallized from isopropyl ether. Yld: 28.2 g (80%), m.p. 55°-56° C.

b) 2-(3,4-Dichlorophenoxy)acetamidine

Obtained using the procedure described in section b of Example 2,starting with 28.2 g (0.12 mole) of methyl2-(3,4-dichlorophenoxy)acetimidate and 10.2 g (0.60 mole) of ammonia in480 ml of absolute ethanol. Reaction time: 3 hours. Yld: 26.3 g(quantitative).

c) 4-Amino-2-[(3,4-dichlorophenoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 9.6 g (0.080 mole) of 3-amino-2-pyrazinecarbonitrile and26.3 g (0.12 mole) of 2-(3,4-dichlorophenoxy)acetamidine in 520 ml ofabsolute ethanol. Refluxing time: 3 hours. Yld: 18.0 g (70%), m.p.261°-263° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.9 Cl.sub.2 N.sub.5 O (F = 322.15)                   C %  H %        Cl %    N %                                         ______________________________________                                        calculated  48.47  2.82       22.01 21.74                                     found       48.50  2.85       22.31 21.65                                     ______________________________________                                    

NMR (CF₃ COOD): δ=5.4 (2H, s); 6.9-7.6 (3H, m); 9.2 (2H, s).

d) 2-[(3,4-Dichlorophenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 15.0 g (0.0466 mole) of4-amino-2-[(3,4-dichlorophenoxy)methyl]pteridine in 1500 ml of 5%aqueous sodium hydroxide. Heating time: 6 hours under reflux. Yld: 10.0g (66%), m.p. 285°-287° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.13 H.sub.8 Cl.sub.2 N.sub.4 O.sub.2 (FW =          323.14)                                                                                 C %  H %        Cl %    N %                                         ______________________________________                                        calculated  48.32  2.50       21.94 17.34                                     found       48.55  2.51       21.91 16.89                                     ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (CF₃ COOD): δ=5.6 (2H, s); 7.0-7.7 (3H, m); 9.3 (1H, d); 9.4 (1H,d).

Example 17 2-[(4-Methoxyphenoxy)methyl]-4(3H)-pteridinone a) Methyl2-(4-methoxyphenoxy)acetimidate

Obtained using the procedure described in section a of Example 16,starting with 27.3 g (0.167 mole) of (4-methoxyphenoxy)acetonitrile[prepared according to K. J. S. Arora et al., J. Chem. Soc. C 1971,2865] and 0.38 g (0.0167 gram-atom) of sodium in 275 ml of methanol.Reaction time: 24 hours. Yld: 23.9 g (73%), m.p. 95°-96° C. (isopropylether).

b) 2-(4-Methoxyphenoxy)acetamidine

23.9 g (0.122 mole) of methyl 2-(4-methoxyphenoxy)acetimidate are addedto a solution, maintained at 10° C., of 10.4 g (0.61 mole) of ammonia in480 ml of absolute ethanol. The reaction mixture is left for 2 days atroom temperature and the excess ammonia is then driven off with a streamof nitrogen. The solution obtained is used in the next step withoutfurther purification.

c) 4-Amino-2-[(4-methoxyphenoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 9.8 g (0.082 mole) of 3-amino-2-pyrazinecarbonitrile andthe above solution of 2-(4-methoxyphenoxy)acetamidine in absoluteethanol. Refluxing time: 2 hours. Yld: 5.5 g (24%), m.p. 238°-240° C.(ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.13 N.sub.5 O.sub.2 (FW = 283.29)                    C %        H %    N %                                               ______________________________________                                        calculated  59.36        4.63   24.72                                         found       59.21        4.62   24.71                                         ______________________________________                                    

NMR (DMSO-d₆): δ=3.7 (3H, s); 5.0 (2H, s); 6.9 (4H, s); 8.3 (2H, peakexchangeable with CF₃ COOD); 8.8 (1H, d); 9.0 (1H, d).

d) 2-[(4-Methoxyphenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 5.5 g (0.0194 mole) of4-amino-2-[(4-methoxyphenoxy)methyl]pteridine in 150 ml of 5% aqueoussodium hydroxide. The solid obtained is taken up in dilute sodiumhydroxide for purification. The insoluble portion is removed byfiltration. The filtrate is acidified with acetic acid to pH 5.5. Theprecipitate formed is isolated by filtration; it is finallyrecrystallized from a mixture of ethanol and N,N-dimethylformamide. Yld:1.7 g (31%), m.p. 233°-234° C.

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.12 N.sub.4 O.sub.3 (FW = 284.27)                    C %        H %    N %                                               ______________________________________                                        calculated  59.15        4.26   19.71                                         found       59.21        4.34   19.39                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=3.7 (3H, s); 5.0 (2H, s); 6.8 (2H, d); 7.0 (2H, d); 8.8(1H, d); 9.0 (1H, d); 13.0 (1H, peak exchangeable with CF₃ COOD).

Example 18 2-[(4-Methoxyphenoxy)methyl]-4(3H)-pteridinone a)4-Amino-2-[(4-methylphenoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 6.9 g (0.057 mole) of 3-amino-2-pyrazinecarbonitrile and14.1 g (0.086 mole) of 2-(4-methylphenoxy)acetamidine [preparedaccording to C. Djerassi and C. R. Scholz, U.S. Pat. No. 2,517,468; C.A.1951, 45, 661f] in 350 ml of absolute ethanol. Refluxing time: 2 hours.Yld: 2.6 g (17%), m.p. 225°-227° C. (acetone/ethanol).

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.13 N.sub.5 O (FW = 267.29)                          C %        H %    N %                                               ______________________________________                                        calculated  62.91        4.90   26.20                                         found       63.22        4.93   26.23                                         ______________________________________                                    

NMR (DMSO-d₆): δ=2.2 (3H, s); 5.0 (2H, s); 6.8 (2H, d); 7.0 (2H, d); 8.3(2H, peak exchangeable with CF₃ COOD); 8.8 (1H, d); 9.0 (1H, d).

b) 2-[(4-Methylphenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 2.5 g (0.0094 mole) of4-amino-2-[(4-methylphenoxy)methyl]pteridine in 68.1 ml of 5% aqueoussodium hydroxide. Heating time: 3 hours 15 minutes at 85° C. Yld: 1.3 g(52%), m.p. 232°-233° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.12 N.sub.4 O.sub.2 (FW = 268.28)                    C %        H %    N %                                               ______________________________________                                        calculated  62.68        4.51   20.88                                         found       62.89        4.54   21.29                                         ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=2.2 (3H, s); 5.0 (2H, s); 6.9 (2H, d); 7.1 (2H, d); 8.8(1H, d); 9.0 (1H, d); 12.9 (1H, peak exchangeable with CF₃ COOD).

Example 19 2-Benzylthiomethyl-4(3H)-pteridinone a)4-Amino-2-(benzylthiomethyl)pteridine

A suspension of 2.3 g (0.019 mole) of 3-amino-2-pyrazinecarbonitrile and5.2 g (0.029 mole) of 2-(benzylthio)acetamidine [prepared according toJ. M. McManus, J. Heterocycl. Chem. 1968, 5, 137] in 150 ml of absoluteethanol is refluxed for 2 hours. After cooling, the solution obtained isconcentrated to dryness under reduced pressure. The residue is washedwith isopropyl ether and dried under reduced pressure. An amorphoussolid is obtained, and is used in the next step without furtherpurification. Yld: 5.4 g (quantitative).

b) 2-Benzylthiomethyl-4(3H)-pteridinone

Obtained using the procedure described in section b of Example 9,starting with 5.4 g (0.019 mole) of4-amino-2-(benzylthiomethyl)pteridine in 400 ml of 5% aqueous sodiumhydroxide. Reaction time: 7 hours at 85° C. Yld: 1.7 g (31%), m.p.224°-226° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.14 H.sub.12 N.sub.4 OS (FW = 284.34)                          C %  H %        N %    S %                                         ______________________________________                                        calculated   59.14  4.25       19.70                                                                              11.28                                     found        58.92  4.35       20.02                                                                              11.10                                     ______________________________________                                    

IR: ν(C=O)=1690 cm⁻¹

NMR (DMSO-d₆): δ=3.6 (2H, s exchangeable with CF₃ COOD); 3.9 (2H, s);7.0-7.5 (5H, m); 8.8 (1H, d); 9.0 (1H, d); 12.8 (1H, peak exchangeablewith CF₃ COOD).

Example 20 2-Ethoxymethyl-6-methyl-4(3H)-pteridinone a) Ethyl2-ethoxyacetimidate

A solution of 604 g (8.0 moles) of chloroacetonitrile in 1200 ml ofabsolute ethanol is added dropwise to a solution, maintained at 80° C.,of sodium ethoxide in ethanol, obtained from 193.2 g (8.4 gram-atoms) ofsodium and 4 l of absolute ethanol. The reaction mixture is allowed toreturn to room temperature; stirring is continued for 2 days. The excesssodium ethoxide is then neutralized with a stream of carbon dioxide. Theprecipitate formed is removed by filtration and washed with ether. Thefiltrate and the ethereal wash solution are combined and concentratedunder reduced pressure. A new precipitate is formed and is removed byfiltration. The filtrate is distilled under reduced pressure Yld: 597.6g (57%), b.p.₁₅₋₂₄ 47°-52° C.

NMR (CDCl₃ +CF₃ COOD):δ=1.1 (3H, t); 1.2 (3H, t); 3.4 (2H, q); 3.7 (2H,s); 4.1 (2H, q).

b) 2-Ethoxyacetamidine

Obtained using the procedure described in section b of Example 17,starting with 29.4 g (0.224 mole) of ethyl 2-ethoxyacetimidate and 21.2g (1.24 moles) of ammonia in 590 ml of absolute ethanol.

c) 4-Amino-2-ethoxymethyl-6-methylpteridine

A suspension of 15.1 g (0.113 mole) of3-amino-6-methyl-2-pyrazinecarbonitrile [prepared according to E. C.Taylor et al., J. Am. Chem. Soc. 1973, 95, 6413] in the above ethanolicsolution of 2-ethoxyacetamidine is refluxed for 2 hours. After cooling,the solution obtained is concentrated to dryness under reduced pressure.The residue is purified by washing with acetone and recrystallizationfrom a mixture of acetone and isopropyl ether Yld: 8.4 g (34%), m.p.166°-168° C.

    ______________________________________                                        Percentage analysis: C.sub.10 H.sub.13 N.sub.5 O (FW = 219.25)                          C %        H %    N %                                               ______________________________________                                        calculated  54.78        5.98   31.94                                         found       54.63        6.02   32.10                                         ______________________________________                                    

NMR (DMSO-d₆): δ=1.1 (3H, t); 2.6 (3H, s); 3.6 (2H, q); 4.4 (2H, s); 8.0(2H, peak exchangeable with CF₃ COOD); 8,9 (1H, s).

d) 2-Ethoxymethyl-6-methyl-4(3H)-pteridinone

A suspension of 7.4 g (0.0338 mole) of4-amino-2-ethoxymethyl-6-methylpteridine in 148 ml of 5% aqueous sodiumhydroxide is brought slowly to 85° C. and maintained at this temperaturefor 2 hours. A further 592 ml of 5% aqueous sodium hydroxide are thenadded and heating is continued at 85° C for 1 hour. After cooling, thesolution obtained is acidified with acetic acid to pH 5.5, and is thenextracted with dichloromethane. The organic extracts are dried oversodium sulphate and concentrated to dryness under reduced pressure. Thesolid residue is recrystallized from acetone in the presence of Norit.Yld: 4.9 g (66%), m.p. 181°-183° C.

    ______________________________________                                        Percentage analysis: C.sub.10 H.sub.12 N.sub.4 O.sub.2 (FW = 220.23)                    C %        H %    N %                                               ______________________________________                                        calculated  54.54        5.49   25.44                                         found       54.39        5.49   25.22                                         ______________________________________                                    

IR: ν(C=O)=1670 cm⁻¹

NMR (DMSO-d₆): δ=1.2 (3H, t); 2.6 (3H, s); 3.6 (2H, q); 4.4 (2H, s); 8.8(1H, s); 13.8 (1H, peak exchangeable with CF₃ COOD).

Example 21 2-[(2-Acetoxyethoxy)methyl]-4(3H)-pteridinone a) Ethyl2-(2-hydroxyethoxy)acetimidate

55.7 g (0.389 mole) of (2-acetoxyethoxy)acetonitrile [prepared accordingto S. W. Schneller et al., Croat. Chem. Acta 1986, 59, 307] are added toa solution, maintained at 10° C, of sodium ethoxide in ethanol, obtainedfrom 0.89 g (0.0389 gram-atom) of sodium and 560 ml of absolute ethanol.The reaction mixture is allowed to return to room temperature; stirringis continued for 3 days. The excess sodium ethoxide is then neutralizedwith a stream of carbon dioxide. The precipitate formed is removed byfiltration and washed with ether. The filtrate and the ethereal washsolution are combined and concentrated under reduced pressure at 30° C.The residue obtained is taken up with 800 ml of ether. On cooling, a newprecipitate is formed and removed by filtration. The filtrate isconcentrated under reduced pressure at a temperature below 30° C. Theliquid obtained is used in the next step without further purification.Yld: 39.2 g (68%).

NMR (CDCl₃ +D₂ O): δ=1.3 (3H, t); 3.3-3.9 (4H, m); 3.9 (2H, s); 4.2 (2H,q).

b) 2-(2-Hydroxyethoxy)acetamidine

Obtained using the procedure described in section b of Example 17,starting with 39.2 g (0.266 mole) of ethyl2-(2-hydroxyethoxy)acetimidate and 22.6 g (1.33 moles) of ammonia in1080 ml of absolute ethanol.

c) 4-Amino-2-[(2-hydroxyethoxy)methyl]pteridine

Obtained using the procedure described in section c of Example 2,starting with 16.0 g (0.133 mole) of 3-amino-2-pyrazinecarbonitrile andthe above solution of 2-(2-hydroxyethoxy)acetamidine in absoluteethanol. Refluxing time: 2 hours 30 minutes. Yld: 20.5 g (70%), m.p.149°-151° C. (ethanol). An analytical sample was obtained byrecrystallization from a mixture of acetone and ethanol. M.p. 159°-161°C.

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.11 N.sub.5 O.sub.2 (FW = 221.22)                     C %        H %    N %                                               ______________________________________                                        calculated  48.86        5.01   31.66                                         found       48.83        5.02   31.32                                         ______________________________________                                    

NMR (DMSO-d₆): δ=3.6 (4H, s); 4.5 (2H, s); 4.9 (1H, peak exchangeablewith CF₃ COOD); 8.3 (2H, peak exchangeable with CF₃ COOD); 8.8 (1H, d);9.0 (1H, d).

d) 2-[(2-Acetoxyethoxy)methyl]-4(3H)-pteridinone

A solution of 10.0 g (0.0452 mole) of4-amino-2-[(2-hydroxyethoxy)methyl]pteridine in 350 ml of 5% aqueoussodium hydroxide is brought gradually to 85° C and maintained at thistemperature for 1 hour 30 minutes. After cooling, the solution obtainedis acidified with acetic acid to pH 5.5, and is then concentrated todryness under reduced pressure. The residue is taken up in 500 ml ofisopropanol. The insoluble inorganic portion is removed by filtration.The isopropanolic solution is concentrated to dryness under reducedpressure. The solid residue is treated with 250 ml of acetic anhydrideand this mixture is refluxed for 1 hour. After cooling, inorganic saltsare removed by filtration; the filtrate is concentrated to dryness underreduced pressure. The residue is purified by 4 successiverecrystallizations from ethanol in the presence of Norit. Yld: 1.2 g(10%), m.p. 157°-159° C.

    ______________________________________                                        Percentage analysis: C.sub.11 H.sub.12 N.sub.4 O.sub.4 (FW = 264.24)                    C %        H %    N %                                               ______________________________________                                        calculated  50.00        4.58   21.20                                         found       50.05        4.75   21.08                                         ______________________________________                                    

IR: ν(C=O)=1690 and 1720 cm⁻¹

NMR (DMSO-d₆): δ=2.0 (3H, s); 3.7-4.0 (2H, m); 4.1-4.4 (2H, m); 4.5 (2H,s); 8.8 (1H, d); 9.0 (1H, d); 12.6 (1H, peak exchangeable with CF₃COOD).

Example 222-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]-4(3H)-pteridinone a)Ethyl 2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate hydrochloride

Obtained using the procedure described in section a of Example 6,starting with 30.4 g (0.130 mole) of(4-acetyl-3-hydroxy-2-propylphenoxy)acetonitrile [prepared according toW. S. Marshall et al., J. Med. Chem. 1987, 30, 682] and 6.6 g (0.143mole) of absolute ethanol in 500 ml of ether. Reaction time: 16 hours.After the reaction mixture has been poured into 1 l of ether, thereaction product is isolated by filtration. Yld: 40.0 g (97%), m.p.157°-159° C.

NMR (DMSO-d₆): δ=0.9 (3H, t); 1.1-1.9 (2H, m); 1.4 (3H, t); 2.4-2.9 (2H,m); 2.6 (3H, s); 4.6 (2H, q); 5.3 (2H, s); 6.7 (1H, d); 7.8 (1H, d);10.8 (2H, peak exchangeable with CF₃ COOD); 12.8 (1H, s exchangeablewith CF₃ COOD).

b) Ethyl 2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate

10.2 g (0.121 mole) of sodium hydrogen carbonate are added to asuspension of 40.0 g (0.127 mole) of ethyl2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate hydrochloride in 1 lof chloroform, and this mixture is stirred for 1 hour. The solid isremoved by filtration and the filtrate is concentrated to dryness underreduced pressure. The residue obtained is extracted with a mixture of100 ml of hexane and 100 ml of isopropyl ether under reflux. Thisextract, concentrated under reduced pressure, is recrystallized fromhexane. Yld: 25.0 g (70%), m.p. 50°-52° C.

NMR (CDCl₃ +D₂ O): δ=1.0 (3H, t); 1.1-1.9 (2H, m); 1.4 (3H, t); 2.6 (3H,s); 2.7 (2H, t); 4.3 (2H, q); 4.7 (2H, s); 6.3 (1H, d); 7.6 (1H, d);12.7 (1H, s partially exchanged).

c) 2-(4-Acetyl-3-hydroxy-2-propylphenoxy)acetamidine

Obtained using the procedure described in section b of Example 17,starting with 25.0 g (0.0895 mole) of ethyl2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate and 7.6 g (0.45 mole)of ammonia in 300 ml of absolute ethanol.

d) 2-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-aminopteridine

Obtained using the procedure described in section c of Example2,starting with 3.6 g (0.030 mole) of 3-amino-2-pyrazinecarbonitrile andthe above solution of 2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetamidinein absolute ethanol. Refluxing time: 6 hours. Yld: 3.2 g (30%), m.p.178°-180° C. (ethanol/N,N-dimethylformamide).

An analytical sample was obtained by a further recrystallization from amixture of ethanol and N,N-dimethylformamide. M.p. 179°-181° C.

    ______________________________________                                        Percentage analysis: C.sub.18 H.sub.19 N.sub.5 O.sub.3 (FW = 353.38)                    C %        H %    N %                                               ______________________________________                                        calculated  61.18        5.42   19.82                                         found       60.96        5.59   19.99                                         ______________________________________                                    

IR: ν(C=O)=1640 cm⁻¹

NMR (DMSO-d₆): δ=0.9 (3H, t); 1.1-1.9 (2H, m); 2.5 (3H, s); 2.5-2.9 (2H,m); 5.2 (2H, s); 6.6 (1H, d); 7.7 (1H, d); 8.3 (2H, peak exchangeablewith CF₃ COOD); 8.8 (1H, d); 9.0 (1H, d); 13.9 (1H, peak exchangeablewith CF₃ COOD).

e) 2-[(4-Acetyl-2-hydroxy-3-propylphenoxy)methyl]-4(3H)-pteridinone

Obtained using the procedure described in section d of Example 2,starting with 1.6 g (0.0045 mole) of2-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-aminopteridine in 32 mlof 5% aqueous sodium hydroxide. Heating time: 1 hour at 90° C. Yld: 1.0g (63%), m.p. 224°-226° C. (ethanol/N,N-dimethylformamide).

    ______________________________________                                        Percentage analysis: C.sub.18 H.sub.18 N.sub.4 O.sub.4 (FW = 354.37)                    C %        H %    N %                                               ______________________________________                                        calculated  61.01        5.12   15.81                                         found       61.12        5.23   15.89                                         ______________________________________                                    

IR: ν(C=O)=1670 and 1690 cm⁻¹

NMR (DMSO-d₆): δ=0.9 (3H, t); 1.0-2.0 (2H, m); 2.4-2.9 (2H, m); 2.5 (3H,s); 5.2 (2H, s); 6.7 (1H, d); 7.7 (1H, d); 8.8 (1H, d); 8.9 (1H, d),12.8 (1H, s exchangeable with CF₃ COOD); 13.0 (1H, peak exchangeablewith CF₃ COOD).

Example 23 7-Hydroxy-2-hydroxymethyl-4(3H)-pteridinone

A mixture of 4.0 g (0.0169 mole) of2-acetoxymethyl-7-hydroxy-4(3H)-pteridinone, 1.2 g (0.0214 mole) ofpotassium hydroxide and 5 ml of water in 80 ml of ethanol is refluxedfor 4 hours. After cooling, the reaction mixture is filtered. The solidthereby isolated is washed with 30 ml of ethanol and taken up in 160 mlof water. The cloudy solution obtained is clarified by filtration andacidified with acetic acid to pH 3.6. The precipitate formed is isolatedby filtration. It is purified by washing with ether andrecrystallization from a mixture of ethanol and N,N-dimethylformamide.Yld: 2.0 g (61%), m.p. >300° C.

    ______________________________________                                        Percentage analysis: C.sub.7 H.sub.6 N.sub.4 O.sub.3 (FW = 194.15)                      C %        H %    N %                                               ______________________________________                                        calculated  43.31        3.12   28.86                                         found       43.27        3.37   28.92                                         ______________________________________                                    

IR: ν(C=O)=1640 and 1675 cm⁻¹

NMR (DMSO-d₆ +CF₃ COOD): δ=4.4 (2H, s); 7.9 (1H, s).

Example 24 7-Hydroxy-2-methoxymethoxymethyl-4(3H)-pteridinone a)2-(Methoxymethoxy)acetamidine

Obtained using the procedure described in section b of Example 17,starting with 14.4 g (0.108 mole) of methyl2-(methoxymethoxy)acetimidate and 7.6 g (0.446 mole) of ammonia in 146ml of anhydrous methanol. Reaction time: 3 days.

b) 4-Amino-7-methoxy-2-(methoxymethoxymethyl)pteridine

Obtained using the procedure described in section c of Example 2,starting with 11.2 g (0.0725 mole) of3-amino-5-chloro-2-pyrazinecarbonitrile[prepared according to E. C.Taylor et al. 1975, 40, 2341] and the above solution of2-(methoxymethoxy)acetamidine in methanol. Refluxing time: 5 hours. Yld:13.2 g (72%), m.p. 193°-195° C.

NMR: (DMSO-d₆): δ=3.3 (3H, s); 4.0 (3H, s); 4.5 (2H, s); 4.7 (2H, s),7.9 (2H, peak exchangeable with CF₃ COOD); 8.4 (1H, s).

c) 4-Amino-7-hydroxy-2-(methoxymethoxymethyl)pteridine

8.1 g (0.0322 mole) of4-amino-7-methoxy-2-(methoxymethoxymethyl)pteridine are added to asolution of 3.2 g (0.080 mole) of sodium hydroxide in 130 ml of water.The suspension obtained is heated at 80° C. for 2 hours. Afterfiltration while hot, the solution is allowed to return to roomtemperature and is then acidified with acetic acid. The precipitateformed is isolated by filtration. It is purified by washing with waterand then with acetone and is recrystallized from a mixture of methanoland N,N-dimethylformamide. Yld: 4.4 g (58%), m.p. 210°-212° C.

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.11 N.sub.5 O.sub.3 (FW = 237.22)                     C %        H %    N %                                               ______________________________________                                        calculated  45.57        4.67   29.52                                         found       45.30        4.53   29.56                                         ______________________________________                                    

NMR (DMSO-d₆): δ=3.3 (3 H, s); 4.4 (2H, s); 4.7 (2H, s); 7.7 (2H, peakexchangeable with CF₃ COOD); 7.9 (1H, s); 12.7 (1H, peak exchangeablewith CF₃ COOD).

d) 7-Hydroxy-2-methoxymethoxymethyl-4(3H)-pteridinone

1.1 g (0.00464 mole) of4-amino-7-hydroxy-2-(methoxymethoxymethyl)pteridine is added to asolution of 1.5 g (0.0267 mole) of potassium hydroxide in 20 ml ofwater. The mixture is refluxed for 8 hours. After cooling, the reactionmixture is acidified with 10% hydrochloric acid to pH 5.5. Theprecipitate formed is isolated by filtration and washed with water. Itis extracted with a mixture of 50 ml of ethanol and 60 ml ofN,N-dimethylformamide under reflux. This extract, concentrated underreduced pressure, is recrystallized from a mixture of ethanol andN,N-dimethylformamide. Yld: 0.2 g (18%), m.p. 224°-226° C. (ethanol).

    ______________________________________                                        Percentage analysis: C.sub.9 H.sub.10 N.sub.4 O.sub.4 (FW = 238.20)                     C %        H %    N %                                               ______________________________________                                        calculated  45.38        4.23   23.52                                         found       45.15        4.11   23.59                                         ______________________________________                                    

IR: ν(C=O)=1625 cm⁻¹

NMR: (DMSO-d₆): δ=3.3 (3H, s); 4.4 (2H, s); 4.7 (2H, s); 7.9 (1H, s);12.8 (2H, peak exchangeable with CF₃ COOD).

Example 25 2-(Ethoxymethyl)-4(3H)-pteridinone a)6-Amino-2-(ethoxymethyl)-4(3H)-pyrimidinone

A stream of ammonia is bubbled into a solution, maintained at 0° C., of75.7 g (0.577 mole) of ethyl 2-ethoxyacetimidate in 650 ml of absoluteethanol so as to dissolve 39.1 g (2.30 moles) of the gas. The solutionobtained is left stirring at room temperature for 2 days. The excessammonia is then driven off with a stream of nitrogen. The reactionmixture is treated with 75.0 g (0.383 mole) of ethyl(1-ethoxyformimidoyl)acetate hydrochloride (prepared according to J. J.Ursprung, U.S. Pat. No. 3,337,579; C.A. 1968, 68, 68986k), and then, atabout 0° C., with 27.3 g (0.401 mole) of sodium ethoxide. After 15minutes at 0° C., the suspended solid is removed by filtration; thefiltrate is stirred for 24 hours at room temperature and is thenrefluxed for 2 hours. This solution is concentrated by the removal of425 ml of ethanol by means of a Dean and Stark apparatus; it is thencooled to about -20° C. The precipitate formed is isolated by filtrationand washed with ethyl ether. The solid obtained is dried and used in thenext step without further purification. Yld: 39.5 g (61%), m.p.224°-226° C. An analytical sample was obtained by recrystallization froma mixture of isopropanol and isopropyl ether. M.p. 228° C.

    ______________________________________                                        Percentage analysis: C.sub.7 H.sub.11 N.sub.3 O.sub.2 (FW = 169.18)                     C %        H %    N %                                               ______________________________________                                        calculated  49.70        6.55   24.84                                         found       49.90        6.21   24.59                                         ______________________________________                                    

IR: ν(C=O)=1610 cm⁻¹

NMR (DMSO-d₆): δ=1.1 (3H, t); 3.5 (2H, q); 4.1 (2H, s); 4.9 (1h,s); 6.4(2H, s exchangeable with CF₃ COOD); 11.2 (1H, s exchangeable with CF₃COOD).

b) 6-Amino-2-(ethoxymethyl)-5-nitroso-4(3H)-pyrimidinone

17.7 g (0.256 mole) of sodium nitrite are added to a solution of 39.5 g(0.233 mole) of 6-amino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 336 ml(0.336 mole) of 1N sodium hydroxide. A solution of 17.9 ml (0.320 mole)of 96% sulphuric acid diluted in 179 ml of water is then added dropwiseat between 0° and 5° C. The precipitate formed is isolated by filtrationimmediately after completion of the addition. The solid obtained iswashed with cold water and then with ethyl ether. After drying, it isused in the next step without further purification. Yld: 46.2 g(quantitative), m.p. 163°-165° C. An analytical sample was obtained byrecrystallization from methanol. M.p. 166°-167° C.

    ______________________________________                                        Percentage analysis: C.sub.7 H.sub.10 N.sub.4 O.sub.3 (FW = 198.18)                     C %        H %    N %                                               ______________________________________                                        Calculated  42.42        5.09   28.27                                         Found       42.57        5.08   28.40                                         ______________________________________                                    

IR: ν(C=O)=1660 cm⁻¹

NMR (DMSO-d₆): δ=1.15 (3H, t); 3.55 (2H, q); 4.25 (2H, s); 9.15 (1H,peak exchangeable with CF₃ COOD); 11.15 (1H, peak exchangeable with CF₃COOD); 12.15 (1H, peak exchangeable with CF₃ COOD).

c) 2-(Ethoxymethyl)-4(3H)-pteridinone

A solution of 19.1 g (0.11 mole) of sodium dithionite in 88 ml of wateris added dropwise to a suspension, maintained at 20° C., of 10.0 g(0.050 mole) of 6-amino-2-(ethoxymethyl)-5-nitroso-4(3H)-pyrimidinone in50 ml of water. After being stirred for 30 minutes at room temperature,the reaction mixture, still maintained at 20° C., is treated with 47.9 g(0.33 mole) of a 40% aqueous solution of glyoxal. Stirring is continuedfor 20 hours at room temperature. The solution obtained is thenextracted with dichloromethane. These organic extracts are dried oversodium sulphate and concentrated to dryness under reduced pressure. Thesolid residue is recrystallized from methanol in the presence of Norit.Yld: 6.5 g (63%), m.p. 168°-169° C. The product is identical to thatobtained in Example 1.

Example 26 2-(Ethoxymethyl)-4(3H)-pteridinone a)5,6-Diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone

A mixture of 12.4 g (0.063 mole) of crude6-amino-2-(ethoxymethyl)-5-nitroso-4(3H)-pyrimidinone, not washed withwater, and 1 g of Raney nickel in 430 ml of methanol is introduced intoan autoclave. The initial hydrogen pressure is set at 75 bars; theautoclave is stirred for 2 hours at room temperature. After outgassing,the insoluble portion is isolated by filtration and washed withN,N-dimethylformamide. The combined filtrate and washing solution areconcentrated to dryness under reduced pressure. The residue is washedwith ethyl ether and recrystallized from a mixture of ethanol and water.Yld: 5.0 g (43%), m.p. 173°-175° C.

NMR (DMSO-d₆): δ=1.1 (3H, t); 3.5 (2H, q); 4.1 (2H, s); 5.9 (5H, peakexchangeable with CF₃ COOD).

b) 5,6-Diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone hemimaleate

A mixture of 3.4 g (0.0185 mole) of5,6-diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone, 4.4 g (0.0379 mole) ofmaleic acid, 300 ml of absolute ethanol and 100 ml of methanol isbrought to reflux. The small insoluble portion is removed by filtrationwhile hot. After cooling, the precipitate formed is isolated byfiltration; it is washed with ethyl ether and recrystallized fromabsolute ethanol. Yld: 2.0 g (45%), m.p. 192°-194° C.

    ______________________________________                                        Percentage analysis: C.sub.7 H.sub.12 N.sub.4 O.sub.2. 1/2(C.sub.4            H.sub.4 O.sub.4) (FW = 242.235)                                                         C %        H %    N %                                               ______________________________________                                        calculated  44.63        5.83   23.13                                         found       44.62        5.73   23.47                                         ______________________________________                                    

NMR (DMSO-d₆ +CF₃ COOD): δ=1.1 (3H, t); 3.45 (2H, q); 4.15 (2H, s); 6.15(1H, s).

c) 2-(Ethoxymethyl)-4(3H)-pteridinone

3.5 g (0.024 mole) of a 40% aqueous solution of glyoxal are added to asuspension of 3.7 g (0.020 mole) of5,6-diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 30 ml of water. Themixture is brought gradually to reflux and kept refluxing for 1 hour.After the addition of Norit, refluxing is continued for a further 10minutes and the reaction mixture is then filtered. The aqueous solutionobtained is extracted with dichloromethane. These organic extracts aretreated as in section c of Example 25. Yld: 2.5 g (61%), m.p. 168°-169°C. The product is identical to that obtained in Example 1.

We claim:
 1. A 4(3H)-pteridinone compound selected from the groupconsisting of 2-methoxymethyl-4(3H)-pteridinone;2-ethoxymethyl-4(3)-pteridinone; 2-propoxymethyl-4(3H)-pteridinone;2-phenoxymethyl-4(3H)-pteridinone; 2-benzyloxymethyl-4(3H)-pteridinone;2-ethoxymethyl-7-hydroxy-4(3H)-pteridinone; and a pharmaceuticallyacceptable alkali metal salt thereof.
 2. A compound in accordance withclaim 1, 2-methoxymethyl-4(3H)-pteridinone, or a pharmaceuticallyacceptable alkali metal salt thereof.
 3. A compound in accordance withclaim 1, 2-methoxymethyl-4(3H)-pteridinone, or a pharmaceuticallyacceptable alkali metal salt thereof.
 4. A compound in accordance withclaim 1, 2-propoxymethyl-4(3H)-pteridinone, or a pharmaceuticallyacceptable alkali metal salt thereof.
 5. A compound in accordance withclaim 1, 2-phenoxymethyl-4(3H)-pteridinone, or a pharmaceuticallyacceptable alkali metal salt thereof.
 6. A compound in accordance withclaim 1, 2-benzyloxymethyl-4(3H)-pteridinone, or a pharmaceuticallyacceptable alkali metal salt thereof.
 7. A compound in accordance withclaim 1, 2-ethoxymethyl-7-hydroxy-4(3H)-pteridinone, or apharmaceutically acceptable alkali metal salt thereof.